Sodium‐glucose co‐transporter‐2 inhibitor treatment in essential thrombocythemia: Impact on hemoglobin/hematocrit levels and outcomes among 11 consecutive patients
Authors: Naseema Gangat, Kaaren Reichard, Ayalew Tefferi
Journal: American Journal of Hematology (2023)

Over the last decade, sodium-glucose co-transporter-2 inhibitors (SGLT-2I), referred to as "gliflozins," have gained widespread popularity for not only the management of diabetes mellitus but also heart failure with or without reduced ejection fraction and chronic renal disease.1 Drugs in the SGLT-2I class include canagliflozin, empagliflozin, dapagliflozin, and ertugliflozin, all of which invariably result in a dose-dependent increase in hemoglobin (Hgb) and hematocrit (Hct) levels.2 In general, SGLT-2I induced erythrocytosis is not associated with an increased risk of thrombosis.3-5 On the other hand, in a recent study of SGLT-2I therapy in patients with previously unrecognized JAK2 mutated myeloproliferative neoplasms (MPN), three of nine (33%) patients experienced a total of four thrombotic events that were potentially related to "unmasking" of clonal erythrocytosis. A separate issue with SGLT-2I use in MPN pertains to accurate disease subclassification since the presence of SGLT-2I associated erythrocytosis precludes a clear distinction between polycythemia vera (PV), essential thrombocythemia (ET), and MPN-unclassifiable (MPN-U).6 In general, patients with MPN have an inherent risk of thrombosis; in a Mayo Clinic study of 3023 patients with MPN (n = 1076 ET; n = 665 PV, median follow-up 9.9 and 8.2 years), thrombosis after diagnosis was documented in 21% of ET and 24% of PV patients with arterial and venous thrombosis rates of 15%/14% and 8%/13%, respectively.7 Accordingly, there remains an ongoing safety concern with SGLT-2I use in MPN, particularly, since large prospective randomized trials with SGLT-2I excluded MPN patients.8 In the current study, our primary objective was to determine the change in Hgb and Hct levels, the incidence of Hgb/Hct values exceeding diagnostic thresholds for PV, and clinical outcomes in patients with an established diagnosis of ET, receiving treatment with SGLT-2I. The Mayo Clinic MPN clinical database, which comprises 748 patients with ET diagnosed between June 2001 and July 2021, was queried to identify patients prescribed SGLT2-I for any length of time following ET diagnosis. The study was approved by the Mayo Clinic institutional review board. ET cases were retrospectively reviewed and confirmed to fulfill the International Consensus Classification (ICC) 2022 diagnostic criteria.6 PV patients were excluded from the current study due to confounding effects of phlebotomy on Hgb/Hct levels. The date of the first SGLT-2I use was considered the baseline date. For each patient, baseline Hgb/Hct, peak Hgb/Hct, and absolute change in Hgb/Hct levels following SGLT-2I treatment were determined. All major arterial and venous thrombotic events,9 including timing, Hgb/Hct levels, and active treatment at the time of event, were carefully recorded. Therapeutic interventions for ET were based on treating physician discretion and included antiplatelet therapy, cytoreductive agents, and/or systemic anticoagulation. A total of 11 patients with ET (median age: 72 years, 55% males) received treatment with empagliflozin (n = 9) or dapagliflozin (n = 2) between March 2016 and December 2022. JAK2V617F mutation was detected in 8 cases (variant allele frequency (VAF); median, 5%, range, 1%–41%) and CALR mutation in 3 patients (Type 1 CALR, n = 2). A history of thrombosis was documented in 7 (64%) of patients, which included four arterial and three venous thrombotic events. Presenting median (range) values at the time of ET diagnosis were 14 g/dL (12.5–14.7) for Hgb, 42.8% (37.4–46) for Hct, 10.7 × 109/L (10.1–11.5) for leukocyte count, and 651 × 109/L (598–828) for platelet count. None of the patients in our study had erythrocytosis prior to starting SGLT-2I. Treatments for ET included aspirin (n = 10), cytoreductive therapy (n = 10), and systemic anticoagulation (n = 4). Supplemental Table 1 provides detailed clinical and laboratory characteristics of 11 patients with ET treated with SGLT-2I. SGLT-2I was initiated at a median of 18.6 months (range; 1.1–256 months) following ET diagnosis, and all 11 patients displayed increase in Hgb/Hct levels without change in leukocyte or platelet count. Baseline median (range) values prior to SGLT-2I were 12.8 g/dL (9.5–14.9) for Hgb, and 38.9% (30.3–44.6) for Hct. Peak median (range) values for Hgb/Hct, recorded at a median of 4.5 months (1–27) following SGLT-2I therapy, included 14.5 g/dL (11–16.4) and 44.4% (34.8–51.1) for Hgb and Hct, respectively, resulting in a baseline increase in Hgb/Hct levels of 1.5 g/dL (1–4)/5.1% (2.6–13.8). Furthermore, Hgb/Hct levels decreased to a median of 12.4 g/dL/38.4% in all three patients in whom SGLT-2I was discontinued (Figure 1). We did not find a significant correlation between presence of JAK2 mutation (p = 0.54), JAK2 VAF (p = 0.20), baseline Hct (p = 0.80), or serum erythropoietin (Epo) level (p = 0.48) and increase in Hct. At a median treatment duration of 17.7 months (4.9–56.4), only one patient experienced aterial thrombosis (myocardial infarction); peak Hgb/Hct and Hgb/Hct at the time of thrombotic event were 14 g/dL/43.1% and 11.4 g/dL/37.7%, respectively; active treatment at the time of event included aspirin and hydroxyurea. Figure 1 highlights Hgb/Hct changes from baseline to peak Hgb/Hct levels in all 11 ET patients receiving SGLT-2I and also includes follow-up Hgb/Hct values in 3 patients in whom SGLT-2I was discontinued. Notably, two patients (Patients 7 and 8) exceeded the proposed ICC Hgb/Hct diagnostic threshold for PV; 16.5 g/dL/49% and 16 g/dL/48% in Caucasian males and females, respectively. Patient 7, a 90-year-old gentleman with JAK2V167F mutated ET without history of thrombosis on aspirin and hydroxyurea, received dapagliflozin 5 mg daily for diabetes mellitus. Baseline Hgb/Hct was 14 g/dL/44.6%; however, three months after initiation of SGLT-2I, peak Hgb/Hct level of 15.9 g/dL/50.1% was observed. His clinical course was uneventful with resolution of erythrocytosis (Hgb/Hct 12.4/38.4) following discontinuation of SGLT2I. In the second case, Patient 8, a 51-year-old female with JAK2V167F mutated ET history of pulmonary embolism and deep venous thrombosis on active treatment with aspirin, apixaban, and hydroxyurea, with a baseline Hgb/Hct 14.9 g/dL/44.1%, was initiated on empagliflozin 10 mg daily for heart failure and chronic renal disease. Three months following SGLT-2I use, peak Hgb/Hct levels of 16.4 g/dL/51.1% were recorded; however, no thrombotic events occurred while on therapy. An additional noteworthy finding, in relation to the maximal increase in Hgb/Hct level, was seen in Patient 5, a 72-year-old gentleman with Type 1 CALR mutated ET, history of venous thrombosis on apixaban and hydroxyurea who received empagliflozin 10 mg daily for heart failure. A significant increase in Hgb and Hct of 4 g/dL and 13.8% was observed four months following SGLT-2I therapy (baseline Hgb/Hct: 11.3/34, peak Hgb/Hct: 15.3/47.8), regardless of which he remained thrombosis-free. In the current study, we demonstrate that all ET patients had an increment in Hgb/Hct levels after initiation of SGLT-2I; moreover, Hgb/Hct diagnostic threshold for PV was exceeded in 2 of 11 (18%) patients. In ET, presence of JAK2 mutation has been associated with higher Hgb/Hct levels; on the other hand, CALR-mutated ET patients are more likely to display lower hemoglobin and leukocyte counts and a higher platelet count compared to JAK2-mutated cases.10, 11 Intriguingly, the highest absolute increase in Hgb/Hct was observed in an ET patient harboring Type 1 CALR mutation, which suggests an independent impact of SGLT-2I on evolution of erythrocytosis. Future studies should assess changes in serum Epo levels, ferritin, and JAK2/CALR VAF with SGLT-2I treatment. In our study, only one patient experienced thrombosis while on SGLT-2I; however, it is to be noted that the majority of patients were already receiving treatment with antiplatelet and cytoreductive agents, which might have had a salutary effect.12 Future studies should assess changes in serum Epo levels, ferritin, and JAK2 VAF with SGLT-2I treatment. Our findings identify erythrocytosis as a universal phenomenon in ET patients treated with SGLT-2I. In the absence of data from controlled trials, our observational study provides novel information that may warrant increased clinical vigilance until larger studies can better characterize the risk of erythrocytosis and thrombosis in ET patients receiving SGLT-2I therapy. Accordingly, routine assessment of Hgb/Hct levels prior to and after initiation of an SGLT-2I in ET patients is advised. Naseema Gangat and Ayalew Tefferi designed the study, collected data, performed analyses, and wrote the paper. Kaaren Reichard reviewed bone marrow biopsies. All authors reviewed the final draft of the paper. None of the authors have any conflicts to disclose. Data available upon request by email to corresponding author. Supplemental Table 1. Clinical and laboratory characteristics and outcomes of 11 patients with essential thrombocythemia (ET) treated with sodium-glucose co-transporter-2 inhibitors (SGLT-2I). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.